ELITE: Early Versus Late Intervention Trial With Estradiol

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ClinicalTrials.gov Identifier: NCT00114517

Recruitment Status : Completed

First Posted : June 16, 2005

Results First Posted : June 8, 2017

Last Update Posted : January 18, 2023

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Sponsor:

Collaborator:

National Institute on Aging (NIA)

Information provided by (Responsible Party):

Howard N. Hodis, M.D., University of Southern California

Study Description

Brief Summary:

The purpose of this study is to examine the effects of oral 17B-estradiol (estrogen) on the progression of early (subclinical) atherosclerosis and cognitive decline in healthy postmenopausal women.

Condition or disease	Intervention/treatment	Phase
Atherosclerosis	Drug: 17B-estradiol Other: Placebo	Phase 2

Detailed Description:

The primary hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of early atherosclerosis if initiated soon after menopause when the vascular endothelium (lining of blood vessels) is relatively healthy versus later when the endothelium has lost its responsiveness to estrogen. Ultrasonography will be used to measure the rate of change in the thickness of the carotid artery and cardiac computed tomography (CT) will be used to measure coronary artery calcium and coronary artery lesions. The second hypothesis to be tested is that 17B-estradiol (estrogen) will reduce the progression of cognitive decline if initiated soon after menopause when healthy brain tissue remains responsive to estrogen versus later when brain tissue has lost its responsiveness to estrogen.

A total of 643 (actual; 504 initially proposed) postmenopausal women were randomized according to their number of years since menopause, less than 6 years or 10 years or more, to receive either oral 17B-estradiol 1 mg daily or matching placebo. Women with a uterus will also use vaginal progesterone gel 4% (or placebo gel) the last ten days of each month. The vaginal progesterone will be distributed in a double-blinded fashion along with the randomized treatment so that only women exposed to active treatment will receive active progesterone. As initially proposed, participants will undergo ultrasonography at baseline and every 6 months throughout the 2 to 5 years (average 3 years) of randomized treatment. Participants will also undergo cognitive testing at baseline and after 3 years of randomized treatment. The trial has been extended for an additional 2 to 2.5 years of randomized treatment (overall average randomized treatment of 5 years and range of 2 to 8.5 years). Ultrasonography will continue to be collected every 6 months and upon completion of randomized treatment, participants will undergo cardiac CT for coronary artery calcium and coronary artery lesion measurements. Participants will also undergo a third cognitive testing at the completion of randomized treatment.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	643 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Biologic Response of Menopausal Women to 17B-Estradiol
Study Start Date :	July 2004
Actual Primary Completion Date :	February 12, 2013
Actual Study Completion Date :	March 5, 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Atherosclerosis

Drug Information available for: Estradiol Estradiol benzoate Estradiol cypionate Estradiol valerate Estradiol acetate Estradiol hemihydrate

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 17B-estradiol Oral 17B-estradiol 1 mg daily	Drug: 17B-estradiol Oral 17B-estradiol 1 mg daily Other Names: Estrace Estrogen Estrogen replacement therapy Hormone replacement therapy Hormone therapy Menopausal hormone replacement therapy
Placebo Comparator: Placebo Matching oral 17B-estradiol placebo daily	Other: Placebo Matching oral 17B-estradiol placebo daily Other Name: Matching placebo

Outcome Measures

Primary Outcome Measures :

Progression of Subclinical Atherosclerosis [ Time Frame: Baseline x 2 and then every 6 months up to 6.7 years ]
Rate of change in distal common carotid artery (CCA) far wall intima-media thickness (mm per year) in computer image processed B-mode ultrasonograms that were obtained at two baseline examinations (averaged to obtain the baseline CIMT value) and every 6 months during trial follow-up.

Secondary Outcome Measures :

Change in Neurocognitive Function (Global Cognition) [ Time Frame: Baseline and at 2.5 years and 5 years ]
All neuropsychological test scores at baseline and follow-up assessments were standardized ([raw score - mean score]/standard deviation) using the baseline means and standard deviations from the entire ELITE sample. Each of three cognitive composite scores was calculated at baseline and follow-up assessments as the weighted average of the individual donor standardized test scores, weighted by the inverse correlation among tests.The change from baseline (endpoint minus baseline cognitive outcome) was computed for each of the cognitive scores (verbal memory, global cognition, and executive functions). Since the outcome is not a single test but a weighted average of multiple tests, the range is not standard and not reported. Higher scores mean better outcomes.
Coronary Artery Calcium [ Time Frame: End of randomized treatment, up to 6.7 years ]
Number of participants with coronary artery calcium measured by cardiac computed tomography

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Older Adult
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Women with a serum estradiol level 25 pg/ml or less
No period for 6 months or more
Postmenopausal less than 6 years, OR 10 years or longer

Exclusion Criteria:

Clinical signs, symptoms, or personal history of cardiovascular disease
Women who have had a hysterectomy only and no oophorectomy (since time from menopause cannot be determined)
Diabetes mellitus or fasting serum glucose 140 mg/dL or greater
Uncontrolled hypertension (diastolic blood pressure 110 mmHg or greater)
Thyroid disease (untreated)
Serum creatinine greater than 2.0 mg/dL
Plasma triglyceride levels greater than 500 mg/dL
Life threatening disease with prognosis less than 5 years
Cirrhosis or liver disease
History of deep vein thrombosis or pulmonary embolism
History of breast cancer
Current hormone replacement therapy (HRT)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00114517

Locations

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United States, California
Atherosclerosis Research Unit, University of Southern California
Los Angeles, California, United States, 90033

Sponsors and Collaborators

University of Southern California

National Institute on Aging (NIA)

Investigators

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Principal Investigator:	Howard N. Hodis, M.D.	Atherosclerosis Research Unit, University of Southern California

More Information

Publications of Results:

Hodis HN, Mack WJ, Henderson VW, Shoupe D, Budoff MJ, Hwang-Levine J, Li Y, Feng M, Dustin L, Kono N, Stanczyk FZ, Selzer RH, Azen SP; ELITE Research Group. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med. 2016 Mar 31;374(13):1221-31. doi: 10.1056/NEJMoa1505241.

Henderson VW, St John JA, Hodis HN, McCleary CA, Stanczyk FZ, Shoupe D, Kono N, Dustin L, Allayee H, Mack WJ. Cognitive effects of estradiol after menopause: A randomized trial of the timing hypothesis. Neurology. 2016 Aug 16;87(7):699-708. doi: 10.1212/WNL.0000000000002980. Epub 2016 Jul 15.

Other Publications:

Hodis HN, Mack WJ, Shoupe D, Azen SP, Stanczyk FZ, Hwang-Levine J, Budoff MJ, Henderson VW. Methods and baseline cardiovascular data from the Early versus Late Intervention Trial with Estradiol testing the menopausal hormone timing hypothesis. Menopause. 2015 Apr;22(4):391-401. doi: 10.1097/GME.0000000000000343.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lin F, Pa J, Karim R, Hodis HN, Han SD, Henderson VW, St John JA, Mack WJ. Subclinical carotid artery atherosclerosis and cognitive function in older adults. Alzheimers Res Ther. 2022 May 7;14(1):63. doi: 10.1186/s13195-022-00997-7.

Sriprasert I, Mert M, Mack WJ, Hodis HN, Shoupe D. Use of oral estradiol plus vaginal progesterone in healthy postmenopausal women. Maturitas. 2021 Dec;154:13-19. doi: 10.1016/j.maturitas.2021.09.002. Epub 2021 Sep 5.

Sriprasert I, Kono N, Karim R, Hodis HN, Stanczyk FZ, Shoupe D, Mack WJ. Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy. Obstet Gynecol. 2020 Oct;136(4):675-684. doi: 10.1097/AOG.0000000000004006.

Sriprasert I, Mack WJ, Hodis HN, Allayee H, Brinton RD, Karim R. Effect of ApoE4 Genotype on the Association Between Metabolic Phenotype and Subclinical Atherosclerosis in Postmenopausal Women. Am J Cardiol. 2019 Oct 1;124(7):1031-1037. doi: 10.1016/j.amjcard.2019.06.022. Epub 2019 Jul 15.

Sriprasert I, Hodis HN, Karim R, Stanczyk FZ, Shoupe D, Henderson VW, Mack WJ. Differential Effect of Plasma Estradiol on Subclinical Atherosclerosis Progression in Early vs Late Postmenopause. J Clin Endocrinol Metab. 2019 Feb 1;104(2):293-300. doi: 10.1210/jc.2018-01600.

Karim R, Stanczyk FZ, Brinton RD, Rettberg J, Hodis HN, Mack WJ. Association of endogenous sex hormones with adipokines and ghrelin in postmenopausal women. J Clin Endocrinol Metab. 2015 Feb;100(2):508-15. doi: 10.1210/jc.2014-2834. Epub 2014 Nov 18.

Henderson VW. Aging, estrogens, and episodic memory in women. Cogn Behav Neurol. 2009 Dec;22(4):205-14. doi: 10.1097/WNN.0b013e3181a74ce7.

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Responsible Party:	Howard N. Hodis, M.D., Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology, Professor of Medicine, Population and Public Health Sciences, and Molecular Pharmacology and Toxicology, Director, Atherosclerosis Research Unit, University of Southern California
ClinicalTrials.gov Identifier:	NCT00114517
Other Study ID Numbers:	AG0025 R01AG024154 ( U.S. NIH Grant/Contract )
First Posted:	June 16, 2005 Key Record Dates
Results First Posted:	June 8, 2017
Last Update Posted:	January 18, 2023
Last Verified:	December 2022

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No
Product Manufactured in and Exported from the U.S.:	No

Keywords provided by Howard N. Hodis, M.D., University of Southern California:


atherosclerosis CAD cardiac computed tomography cardiovascular disease carotid artery intima-media thickness cognitive function computed tomography coronary artery calcium coronary artery disease coronary artery lesions CVD	estrogen estrogen therapy hormone therapy postmenopausal subclinical vascular disease timing hypothesis ultrasonography menopausal hormone replacement therapy menopause prevention intervention

Additional relevant MeSH terms:

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Atherosclerosis Arteriosclerosis Arterial Occlusive Diseases Vascular Diseases Cardiovascular Diseases	Hormones Estradiol Estrogens Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs

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